Despite the widespread use of highly active antiretroviral therapy (HAART), HIV-associated neurocognitive disorders remain surprisingly common in both adults and children. Moreover, it is becoming clear that despite HAART, HIV and the closely-related simian immunodeficiency virus (SIV) persist in the brain 'sanctuary', where access of otherwise potent antiretrovirals is limited. However, the mechanisms that establish and maintain HIV infection in the brain during HAART are largely unknown. The overall goal of this proposal is to explore the role of long-lived brain perivascular macrophages (PVM) as a significant source of SIV infection and inflammation in the brain of SIV-infected infant macaques receiving suppressive antiretroviral therapy (ART). In our previous studies, we demonstrated that monocyte turnover predicts the onset of AIDS and is correlated with severity of SIV encephalitis in the SIV macaque model. Recently we have reported for the first time depletion of brain PVM in SIV-infected macaques with intrathecally administered liposome-encapsulated bisphosphonates. Our central hypothesis is that PVM are a significant source of persistent CNS infection and inflammation in HIV-infected newborns starting HAART with high monocyte turnover. The first aim will determine whether initiating ART after the monocyte turnover increases above pre-infection baseline levels will affect PVM infection and brain and CSF viral loads. The second aim will focus on ablating PVM in the setting of ART-treated chronic SIV infection. This study will result in better characterization of brain PVM (e.g., phenotypic markers, turnover and infection) that will help develop eradication therapy, tailored directly for the brain, and for targeting these cells selectively. The research proposed in this application is innovative because it represents an entirely novel departure from the current approach to maintaining viral suppression in HIV- infected children. Our contribution here will be significant because it is a first step toward the development of therapeutic strategies for targeting virus-infected PVM or inhibiting viral infection of PVM. Once such strategies become available, there is promise that persistent HIV reservoirs could be eradicated from brain and other tissues.